JP5788534B2 - Formulations containing phenylaminopyrimidine derivatives as active agents - Google Patents

Description

INTRODUCTION The present invention relates to phenylaminopyrimidine derivatives represented by the development code NRC-AN-019 (for oral administration, pharmaceutically acceptable salts thereof, and polymorphs such as Form I, Form II and Form III). Oral liquid preparations intended for self-emulsification.

  NRC-AN-019 is chemically defined as (3,5-bis-trifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl. -L] -benzamide, a phenylaminopyrimidine derivative, has been identified as a BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia. NRC-AN-019 has also been found to be an effective compound against other tumors such as head and neck cancer, prostate cancer and the like. Its structural formula is:

It becomes.

NRC-AN-019 is a pale yellow to light brown crystalline to amorphous powder. Its molecular formula _{is C 25 H 17 F 6 N 5} O, its relative molecular mass is 517.44. NRC-AN-019 is hardly soluble in water, very slightly soluble in aqueous buffer at pH 1.2, and insoluble in neutral / alkaline aqueous buffers. The drug substance is soluble in dimethylformamide and dimethyl sulfoxide.

  The present invention relates to an oral dosage form containing a therapeutically effective amount of NRC-AN-019, including pharmaceutically acceptable salts thereof and polymorphs such as Form I, Form II and Form III. The present invention particularly relates to self-emulsifying drug delivery formulations containing NRC-AN-019 in a solution suitable for oral administration. The formulations of the present invention are useful as anti-tumor agents in the treatment of chronic myelogenous leukemia and several other tumors such as head and neck cancer, prostate cancer and the like. The present invention also relates to a method for producing the formulation.

BACKGROUND OF THE INVENTION AND PRIOR ART NRC-AN-019 is a protein-tyrosine kinase inhibitor; it is a BCR-ABL tyrosine kinase that is caused by Philadelphia chromosomal abnormalities and found in chronic myelogenous leukemia (CML) Inhibits dysfunction. NRC-AN-019 inhibits cell proliferation and induces apoptosis (programmed cell death) in BCR-ABL cell lines and in leukemia cells caused by CML. It also works effectively against other tumors such as head and neck cancer, prostate cancer and the like.

  Understand their role in cancer since the first discovery of tyrosine-specific protein kinases encoded by homologous sequences of transforming viruses and their normal cells, and explore their potential as therapeutic targets Had great interest. BCR-ABL tyrosine kinase inhibitors have started the era of molecular targeted therapy, which has become a very breakthrough in the discovery of anticancer drugs.

  Oral drug administration is the most commonly accepted route of administration for the treatment of disease. Lipophilic drugs exhibit low solubility and release rate when administered as conventional tablets or capsules, and thus exhibit lower bioavailability. Therefore, in solving the problem of poor bioavailability of poorly soluble drugs, improving the absorption of orally administered drugs is a key point. In view of drug bioavailability and patient dose-response variability, NRC-AN-019 presents unique difficulties with regard to solubility and its formulation development. The inventors of the present application surprisingly found that lipid-based formulation technology provides a therapeutically effective platform for delivery of NRC-AN-019 in terms of bioavailability and pharmacological response did.

  As inhibitors of BCR-ABL kinase for the treatment of chronic myeloid leukemia, novel phenylaminopyrimidine derivatives are disclosed in US Patent Application No. 20070226333 corresponding to PCT application number PCT / IN05 / 000243. Novel intermediates useful for the preparation of novel phenylaminopyrimidine derivatives are also disclosed in the above-mentioned patent applications.

  The above U.S. patent applications describe, among other things, novel phenylaminopyrimidine derivatives of general formula I for topical, enteral (eg, oral or rectal), or parental administration. Suitable and can be used in the treatment of chronic myelogenous leukemia (CML) with a pharmaceutically acceptable carrier that can be an inorganic or organic solid or liquid. In addition to the active ingredient (s), the pharmaceutical composition of the above-described invention may contain one or more excipients or adjuvants.

  Example 14 of said PCT application number PCT / IN05 / 000243 is Example 1-1: (3-trifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidine-2- Yl-amino) -phenyl] -benzamide and Example-3: (3,5-bistrifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -Phenyl-l] -benzamide discloses a capsule formulation comprising an active compound with lactose, polyvinylpyrrolidone, crospovidone and magnesium stearate as excipients.

  A specific form of (3,5-bistrifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -benzamide is a PCT application number PCT / IN05 / Disclosed in US Patent Application No. 20080306100 corresponding to 000243, the compound is represented by AN-019. The application also discloses a method for its production and a pharmaceutical composition containing this crystalline form, along with its use as an antitumor agent in humans.

  The disclosure of the different polymorph Form I, Form II and Form III is highlighted by US Patent Application No. 20090227611 corresponding to PCT Application Number PCT / IB09 / 005421. Despite all the above forms exhibiting useful pharmacological properties as antitumor activity, it is disclosed that Form III has been found to have better thermodynamic stability. In this specification, the description of Form I, Form II and Form III polymorphs corresponds to the polymorphs described in PCT / IB09 / 005421, the disclosure of which is incorporated herein by reference. Incorporated.

  Phenylaminopyrimidine derivatives are useful for the treatment of BCR-ABL-positive cancers and neoplastic diseases such as leukemia [especially chronic myeloid leukemia (CML), acute lymphoblastic leukemia with known mechanism of apoptosis) It is very well known that it has been found to be very useful. As a result, there has been interest and attention to develop more new molecules, followed by formulations for effective treatment.

  (3,5-bis-trifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidine-), a new phenylaminopyrimidine derivative represented by NRC-AN-019 2-ylamino) -phenyl-l] -benzamide has been described in the prior art and has been identified as a BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia, so that There is a need to develop a dosage form suitable for oral administration for warm-blooded animals.

  None of the prior art describes the use of NRC-AN-019 as an active pharmaceutical ingredient in the formulations of the present invention.

  The capsule formulation disclosed in the embodiment of US Patent Application No. 20070226333 corresponding to PCT Application No. PCT / IN05 / 000243 has been found to have very low absorption properties; therefore, to elicit drug activity There is a need to develop better dosage forms that can provide good bioavailability and optimal blood levels for treatment.

  The development of this new phenylaminopyrimidine derivative is contemplated by our scientists to develop an orally administrable dosage form for better patient compliance.

  For the reasons described above, a need has arisen to develop an orally administrable formulation to increase the bioavailability of this novel phenylaminopyrimidine derivative.

  In one aspect, the present invention provides, in particular, formulations comprising NRC-AN-019 as an active ingredient, the compositions taking the form of solutions. The formulations of the invention practiced herein provide a system that can spontaneously form an emulsion upon contact with gastric juice.

  There is a need to address formulations and methods that are more therapeutic, easier to administer, and economical to produce on a large scale.

OBJECTIVES OF THE INVENTION Accordingly, the main object of the present invention is a BCR-ABL tyrosine kinase inhibitor, which is associated with chronic myelogenous leukemia (CML) and several other tumors such as head and neck cancer and prostate cancer. Orally administrable pharmaceutical composition of NRC-AN-019 (including pharmaceutically acceptable salts thereof and polymorphs such as Form I, Form II and Form III) Design and develop.

  Another object of the present invention is that NRC-AN-019 has unique difficulties associated with its oral administration because of its solubility, bioavailability, and patient dose-response variability. It is to provide an orally administrable pharmaceutical composition in the form.

  Accordingly, a further object of the present invention is to provide an oral liquid pharmaceutical composition in the form of a lipid-based formulation and to achieve higher therapeutic levels in the treatment of the above mentioned diseases.

  More specifically, the present invention aims to develop a method for producing an oral solution comprising NRC-AN-019, lipid phase, surfactant (s) and water miscible solvent.

  Yet another object of the present invention is a method for enhancing the bioavailability of a lipophilic drug in a patient undergoing treatment, the method comprising orally administering the pharmaceutical composition of the present invention to said patient. Is to provide.

  Yet another object of the present invention is to increase the bioavailability of pharmaceutical ingredients following self-emulsification of the formulation after contact with gastric juice during oral administration.

  Yet another object of the present invention is to make the lipophilic phase, surfactant (s), and solvent phase a homogeneous mixture and to add the active agent to form a solution.

  Yet another object of the present invention (solution) is to optionally fill capsules with the formulation of the present invention or absorb onto the surface of any absorbent material, followed by individual dosage forms as tablets or capsules To formulate.

Accordingly, the present invention provides an oral pharmaceutical formulation comprising NRC-AN-019 (including pharmaceutically acceptable salts thereof, and polymorphs thereof, such as Form I, Form II, and Form III); In order to achieve effective treatment for chronic myelogenous leukemia and other tumors such as head and neck cancer and prostate cancer, a production method for enhancing bioavailability is provided.

  The present invention also provides a method for treating cancer, the method comprising administering a pharmaceutical composition of the present invention to a patient in need thereof.

  The present invention also provides a pharmaceutical composition for use in the treatment of the human or animal body.

  The invention also provides the use of a formulation of the invention in the manufacture of a medicament for the treatment of cancer.

FIG. 1 shows a bioavailability study of the formulations of the present invention with respect to the capsule dosage forms disclosed in previous patents and active pharmaceutical ingredients.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising NRC-AN-019 in the form of a self-emulsifying system as an active ingredient useful for the treatment of CML and other tumors such as head and neck cancer and prostate cancer. The system is capable of forming an emulsion in-situ upon contact with gastric fluid after oral administration.

The present invention provides a pharmaceutical composition for oral administration comprising:
(A) A therapeutically effective amount of (3,5-bistrifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) phenyl] benzamide (NRC-AN-019) Or a pharmaceutically acceptable salt thereof;
(B) a lipophilic phase;
(C) at least one pharmaceutically acceptable surfactant; and (d) a pharmaceutically acceptable water-miscible solvent.

  The present invention is chemically synthesized as (3,5-bis-trifluoromethyl) -N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl-1] -benzamide. Applied to the formulation development of NRC-AN-019, known for example as a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, head and neck cancer and prostate cancer, for example. And have been shown to exhibit useful antitumor activity. NRC-AN-019 targets BCR-ABL (protein-tyrosine kinase), an important target for the treatment of chronic myeloid leukemia. Because BCR-ABL kinase controls many cellular processes, including proliferation and survival, and the disordered activity of these enzymes is involved in the malignant transformation of various tumors, certain inhibitors of BCR-ABL kinase, For example, the compound is an attractive therapeutic agent. The development of this compound represents a tremendous research effort that is beginning to show clinically good signs.

  Due to the high hydrophobicity of NRC-AN-019, the bioavailability levels achieved in other oral dosage forms such as capsules, tablets, etc. are low and show a wide variation in therapeutic levels. In order to achieve an effective anti-malignant treatment, the serum concentration of the active compound should be maintained within a certain range and an optimal therapeutic window should be ensured.

  A decisive difficulty causing lower bioavailability problems is, for example, the inherent insolubility of NRC-AN-019 in aqueous media, so it is still necessary for bioavailability while allowing convenient use Contain the drug at a sufficiently effective concentration to meet the required level (eg, to achieve effective absorption from the stomach or intestinal lumen, and to achieve a constant and adequately effective serum concentration) To provide a dosage form capable of

  The major mechanisms by which lipid-based formulations increase bioavailability are via drug solubilization, decreased P-glycoprotein-mediated excretion, increased hepatic first-pass metabolism due to increased lymphatic transport, increased gastrointestinal transit time, or gastrointestinal Includes protection from disassembly in the tube. This helps to absorb quickly and with less variation.

  Typically, in the formulations of the present invention, NRC-AN-019 (including pharmaceutically acceptable salts and polymorphs such as Form I, Form II and Form III) is the total weight of the composition. On the basis of about 0.05 weight percent to about 50 weight percent, preferably about 0.1 weight percent to about 20 weight percent, more preferably about 0.25 weight percent to about 10 weight percent Is done.

The lipophilic phase in the compositions of the present invention typically comprises a pharmaceutically acceptable lipophilic medium such as triglycerides, diglycerides, monoglycerides, fatty acids or derivatives of fatty acids, or mixtures thereof. Typically, the fatty acids have a carboxyl moiety attached to a linear or branched, saturated or unsaturated C ₁ -C ₂₁ aliphatic moiety. A long chain fatty acid comprising a C _{12 to} C ₂₂ fatty acid, wherein the aliphatic moiety comprises 11 to 21 carbon atoms; a medium chain fatty acid comprising a C _{6 to} C ₁₁ fatty acid, A medium chain fatty acid in which the aliphatic moiety contains 5 to 10 carbon atoms; and a short chain fatty acid comprising a C _{2 to} C ₅ fatty acid, wherein the aliphatic moiety contains 1 to 4 carbon atoms Short chain fatty acids are preferred, and long and medium chain fatty acids or their triglycerides are particularly preferred.

  Examples of fatty acids that may be present in the lipophilic phase in the form of free acids or as triglyceride esters, diglyceride esters or monoglyceride esters are acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargon Acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecyl acid, arachidic acid, heneicosyl acid, behenic acid, α-linolenic acid, stearidonic acid, ethyl Examples include icosapentaenoic acid, docosahexaenoic acid, linoleic acid, γ-linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonic acid and ricinoleic acid.

More typically, the lipophilic phase comprises a mixture of monoglycerides, diglycerides and triglycerides, wherein the monoglycerides, diglycerides and triglycerides have C ₁₂ -C ₂₀ fatty acid residues attached to at least one alcohol group on the glyceride moiety. Contains. Preferably, the C ₁₂ -C ₂₀ fatty acid residue is bound to the respective alcohol group of the glyceride moiety. Preferably, the _C 12 _{-C 22} fatty acid residues _{are C} 16 _{~ 18} fatty acid residue. The mixed monoglycerides, diglycerides and triglycerides can carry both saturated and unsaturated fatty acid residues.

In a preferred embodiment, the lipophilic phase in the formulations of the present invention, the unsaturated fatty acid residues, typically include ricinoleic acid, linolenic acid, a C ₁₈ unsaturated fatty acid residues such as linoleic acid and oleic acid. Typically, the unsaturated fatty acid residue is present in an amount of at least 20 weight percent, more preferably at least 40 weight percent or more, based on the total weight of the lipophilic phase. Preferably, saturated fatty acid residues such as stearic acid residues, myristic acid residues and palmitic acid residues are present in an amount of 50 weight percent or less, based on the total weight of the lipophilic phase.

The lipophilic phase in the pharmaceutical composition of the present invention may be obtained by hydrolysis of various animal and vegetable oils, such as olive oil, followed by separation of the liquid acid. A preferred liquid acid thus obtained is (Z) -9-octadecenoic acid, also known as oleic acid. Oleic acid is a monounsaturated omega-9 fatty acid found in a variety of animal and plant sources (the only carbon-carbon double bond occurs at the ninth carbon atom from the free end of the aliphatic moiety. Mean). Oleic acid can be characterized by a specific gravity of 0.889 to 0.895, an acid value of 196 to 204, an iodine value of 85 to 95, a density of 0.895 g / cm ³ , and a melting point of 4 ° C.

  Typically, the lipophilic phase of the pharmaceutical composition of the present invention is from about 5 weight percent to about 85 weight percent, preferably from about 10 weight percent to about 75 weight percent, and more, based on the total weight of the composition. Preferably, it is present in an amount of about 12.5 weight percent to about 65 weight percent.

In a preferred embodiment, the lipophilic phase of the formulations of the present invention, medium chain fatty acids (e.g., caprylic and capric acids and mixtures thereof) monoglycerides, alcohols having C ₈ ~ ₁₀ fatty acids such as diglycerides and monoglycerides / diglycerides Neutral oils such as esters, neutral vegetable oils, especially known under the trade name Miglyol, Miglyol 810 and Miglyol 812 (fractionated coconut oil containing caprylic acid-capric triglyceride), and Miglyol 818 (caprylic acid) -Capric acid-linoleic acid triglyceride), fractionated coconut oil available as Captex 355 (caprylic acid-capric acid triglyceride) and the like. Another suitable caprylic-capric triglyceride is known under the trade name Myritol, including the product Myritol 318, and is commercially available. Further suitable products of this class are Captex 300 (caprylic acid / capric acid triglycerides) and Captex 800 (propylene glycol diethylhexanoate), Neobee M5 (caprylic acid / capric acid triglycerides) and the like.

  In a further preferred embodiment, the lipophilic phase of the formulation of the invention comprises a pharmaceutically acceptable oil, preferably the oil comprises an unsaturated component such as a vegetable oil or fish oil. The lipophilic phase can also be used in the presence of a suitable catalyst in various natural vegetable oils (eg corn oil, kernel oil, almond oil, peanut oil, olive oil, soybean oil, sunflower oil, corn oil, safflower oil and palm oil. Or a mixture thereof) may include suitable transesterified ethoxylated vegetable oils, such as those obtained by reacting a polyethylene glycol having a molecular weight of 200-800. Transesterified ethoxylated vegetable oils are known under the trade names Labrafil (eg, Labrafil M 2125 CS, Labrafil M 1944 CS, Labrafil M 2130 CS) and are commercially available.

  The formulations of the present invention also include one or more pharmaceutically acceptable surfactants. Surfactants promote the value of the balance between hydrophilicity and lipophilicity (HLB) required for emulsification. The surfactant component may comprise a hydrophilic or lipophilic surfactant, or a mixture thereof. Herein, hydrophilic surfactants have an HLB value greater than 10 and lipophilic surfactants have an HLB value less than 10. Nonionic hydrophilic and nonionic lipophilic surfactants are particularly preferred.

  Typically, the hydrophilic surfactant is a surfactant having a relatively high, typically 11-15, more typically 12-14 HLB value, natural or hydrogenated. The reaction product includes, but is not limited to, a reaction product of vegetable oil and ethylene glycol, such as polyoxyethylene glycolated natural or hydrogenated vegetable oil, such as polyoxyethylene glycolated natural or hardened castor Oil. Such products may also be obtained by reacting natural or hydrogenated castor oil and ethylene oxide in a molar ratio of, for example, 1: 5 to about 1: 200 followed by any purification step. The product Cremophor EL is particularly preferred and can be produced by reacting 1 mol of castor oil with 35-40 mol of ethylene oxide, which is chemically known as polyoxyl-35-castor oil.

  Cremophor EL has a saponification number of 65-70, an acid number of ≦ 2.0, an iodine number of 25-35, an HLB value of 12-14, a hydroxyl number of 65-78, a water content (%) of 2.8 (%) Fisher value) and a melting point of 19-20 ° C.

  Other hydrophilic surfactants suitable for use in the present invention include surfactants such as those available under the trade name Nikol HCO-60, which is the reaction product of hydrogenated castor oil and ethylene oxide.

  As further examples of said hydrophilic surfactants, polyoxyethylated sorbitan fatty acid esters, eg products: Tween 20 [polyoxyethylene (20) sorbitan monolaurate], Tween 21 [polyoxyethylene (4) sorbitan monolaur Rate], Tween 40 [polyoxyethylene (20) sorbitan monopalmitate], Tween 60 [polyoxyethylene (20) sorbitan monostearate], Tween 61 [polyoxyethylene (4) sorbitan monostearate], Tween 65 [polyoxyethylene (20) sorbitan tristearate], Tween 80 [polyoxyethylene (20) sorbitan monooleate], Tween 81 [polyoxyethylene (5) sorbitan monooleate], sorbitan mono- and those known under the trade name Tween, including ween 85 [polyoxyethylene (20) sorbitan trioleate], Tween 120 [polyoxyethylene (20) sorbitan monoisostearate], and the like. Polyoxyethylene derivatives of tri-lauryl esters, mono- and tri-palmtyl esters, mono- and tri-stearyl esters or mono- and tri-oleyl esters are included. Preferably, the polyoxyethylene sorbitan fatty acid ester used in the composition of the present invention is Tween 80 [polyoxyethylene (20) sorbitan monooleate], which has a hydroxyl number of 65-80, a 2% acid. And a saponification number of 45-55.

  Other hydrophilic surfactants that can be used are polyoxyethylene fatty acid esters, polyoxyl glycerides, polyoxyethylene-polyoxypropylene copolymers, dioctyl succinate, dioctyl sodium sulfosuccinate or sodium lauryl sulfate, phospholipids (especially , Lecithin), propylene glycol monofatty acid esters and difatty acid esters, bile salts and the like.

  The amount of hydrophilic surfactant used is typically in the range of about 5 weight percent to about 60 weight percent, preferably about 10 weight percent to about 50 weight percent, based on the total weight of the composition. Is within.

  Typically, in other embodiments of the invention, the lipophilic surfactant is, for example, sorbitan-monolauryl ester, sorbitan-monopalmityl ester, sorbitan-monostearyl ester, sorbitan-tristearyl ester, sorbitan Including, but not limited to, sorbitan fatty acid esters of the type known and marketed under the trade name Span, including, but not limited to, mono-oleyl esters and sorbitan-trioleyl esters, typically 5-7 , More typically surfactants having a relatively low HLB value of 4-8.

  Other examples of lipophilic surfactants that can be used in the present invention include transesterification products of natural vegetable oil triglycerides with polyalkylene polyols, monoglycerides, diglycerides and mono / diglycerides (especially caprylic or capric acid with glycerol) Esterified products), sorbitan fatty acid esters, pentaerythritol fatty acid esters and polyalkylene glycol ethers, monoglycerides, glycerol triacetates or triacetins, sterols, derivatives thereof and the like.

  The amount of lipophilic surfactant used is typically in the range of about 5 weight percent to about 60 weight percent, preferably about 10 weight percent to about 50 weight percent of the total weight of the composition.

  Typically, the at least one pharmaceutically acceptable surfactant is at least one said lipophilic surfactant. In another embodiment, the at least one pharmaceutically acceptable surfactant is at least one hydrophilic surfactant. In another embodiment, the at least one pharmaceutically acceptable surfactant is at least one surfactant selected from hydrophilic and lipophilic surfactants. In another embodiment, the at least one pharmaceutically acceptable surfactant is at least one surfactant of a hydrophilic or lipophilic surfactant.

  In one embodiment, the formulation of the present invention comprises at least one of the surfactants described above.

  Typically, the pharmaceutical composition of the present invention comprises a lipophilic or hydrophilic surfactant as the primary surfactant and one or more co-surfactants as defined above. The co-surfactant, when present, can be selected from any surfactant type shown in the surfactant category above. The co-surfactant phase adds to the effectiveness of the main surfactant.

  Preferably, the co-surfactant is (i) partial alcoholysis of vegetable oil with macrogol, (ii) esterification of glycerol and macrogol with unsaturated fatty acids, and (iii) glycerol ester and ethylene oxide condensation It is a polyoxyl glyceride that can be obtained by mixing a product with a fatty acid of vegetable oil. Typically, the polyoxylglycerides used as co-surfactants include mixtures of glycerol monoesters, diesters, and triesters with polyethylene glycol (PEG) monoesters and diesters, preferably 200- Having an average relative molecular weight of 400; Such polyoxyl glycerides can be obtained as a product of partial alcoholysis of medium chain triglycerides with polyethylene glycol, caprylic (octanoic) acid and capric (decane) acid, or with glycerin ester and ethylene oxide condensate It can be obtained by mixing caprylic acid and capric acid.

  Preferred polyoxylglyceride co-surfactants for use in the present invention are those marketed under the trade name Labrasol, such as an acid number of ≦ 2.0, an iodine number of ≦ 2.0, a saponification number of 85-105 and Caprylocaproyl polyoxyl glyceride having a hydroxyl number of 170-205.

  Optionally, other co-surfactants that can be used are the lauroyl polyoxylglyceride marketed under the trade name Gelucire 44/14, the linoleoyl polyoxyl glyceride marketed under the trade name Labrafil M2125CS, and the trademark Labrafil M1944CS. Oleoyl polyoxyl glyceride marketed under the name, stearoyl polyoxyl glyceride marketed under the trade name Gelucire 50/13.

  The cosurfactant, when present, is typically within the range of about 2 weight percent to about 60 weight percent, preferably about 5 weight percent to about 45 weight percent of the total weight of the composition. used.

  In one particularly preferred embodiment, the primary surfactant is polyoxyl 35 castor oil and the one or more co-surfactants are caprylocaproyl polyoxyl 8 glycerides.

  In another particularly preferred embodiment, the primary surfactant is polyoxyl 35 castor oil and the one or more co-surfactants are caprylocaproyl polyoxyl 8 glyceride and polysorbate 80.

  In yet another particularly preferred embodiment, the primary surfactant is polyoxyl 35 castor oil and the one or more co-surfactants are glycerol monocaprylo couplers.

  In yet another particularly preferred embodiment, the primary surfactant is polyoxyl 35 castor oil and the one or more co-surfactants are ethyl oleate.

  The total amount of surfactant phase used is typically in the range of about 4 weight percent to about 70 weight percent, preferably about 8 weight percent to about 60 weight percent of the total weight of the composition.

The formulations of the present invention further comprise a pharmaceutically acceptable water-miscible solvent. The water-miscible solvent used in the present invention acts as a carrier medium for NRC-AN-019, helps solubilize high concentrations of the drug, and promotes water penetration into the formulation. According to the present invention, a particularly preferred solvent comprising a pharmaceutically acceptable water-miscible solvent is an average molecular weight of 570-613, a flash point of 250 ° C., a density of 1.080 g / cm ³ , and a hydroxyl number of 178-197. And α-hydro-ω-hydroxy poly (oxy-1,2-ethanediyl) derivatives having a viscosity of 9.9 to 11.3 mm ² / s (at 98.9 ° C. ± 0.3 ° C.). Particularly preferred is polyethylene glycol having an average molecular weight of 600 and known on the market as POGOL600. Other examples include diethylene glycol monoethyl ether having an average molecular weight of 134.2; a density of 0.988 g / cm ³ ; a hydroxyl number of 300-400, and a boiling point of 197-205 ° C.

  In particular, it has been found that the use of the components defined above results in a composition in which a water-miscible solvent is particularly suitable as an NRC-AN-019 carrier medium.

  Compositions according to formulations comprising the above components as water miscible solvents may, of course, additionally or alternatively include one or more other components as the solvent phase.

Further examples of suitable water miscible solvents include polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol, polyethylene glycol ether, glycerol, propylene glycol, polyethylene glycol, and lower alkanols, especially C ₁ such as ethanol and benzyl alcohol. ˜C ₈ alkanol is included. Although the use of alkanols such as ethanol and / or benzyl alcohol as solvent phase components is contemplated by the inventors of the present invention for several reasons, this is generally less preferred. I will.

  The pharmaceutically acceptable water-miscible solvent can of course include a mixture of two or more different solvents. However, NRC-AN-019 will typically have sufficient solubility in any solvent present in such a mixture so that the effectiveness of the carrier system is not significantly impaired.

  The amount of water miscible solvent present is typically from about 2 weight percent to about 60 weight percent, preferably from about 5 weight percent to about 30 weight percent, more preferably based on the total weight of the composition. About 5.5 weight percent to about 25 weight percent.

  The formulations of the present invention can optionally include one or more antioxidants in a suitable concentration range to prevent acid odor of the lipid phase used in the composition. Suitable antioxidants include α-tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, alkyl gallates such as lauryl gallate or octyl gallate, carotene, Includes carnosic acid and the like.

  Preferably, the antioxidant is an antioxidant that captures free radicals. More preferably, the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, and mixtures thereof. If desired, one or more antioxidants are present in a proportion in the composition of the invention in relation to the stability aspects of the pharmaceutical composition.

  Butylhydroxyanisole and butylhydroxytoluene can be used individually or in combination as antioxidants. When used in combination, they are preferably used in a ratio of 6: 4 to 9: 1, more preferably in a ratio of 7: 3 to 8: 2.

  The butyl hydroxyanisole antioxidant is typically from about 0.01 weight percent to about 5 weight percent, preferably from about 0.02 weight percent to about 3 weight percent, based on the total weight of the composition. Preferably, it is used in the range of about 0.05 weight percent to about 2 weight percent. The amount of butylhydroxytoluene used is typically about 0.001 weight percent to about 4 weight percent, preferably about 0.002 weight percent to about 3 weight percent, based on the total weight of the composition. More preferably, it is in the range of about 0.01 weight percent to about 0.5 weight percent.

  The compositions of the present invention optionally comprise one or more nutritionally acceptable oil-soluble sweeteners. Sweeteners can be used to improve patient acceptance of the dosage form. Typically, the sweetener is selected from mannitol, sodium saccharin, propylene glycol, acesulfame K, sucralose, neotame, aspartame and saccharin. Sweeteners can also enhance the flavor system.

  The amount of sweetener used is typically in the range of about 0.1 weight percent to about 10 weight percent, preferably about 0.25 weight percent to about 5 weight percent, based on the total weight of the composition. Is within.

  The compositions of the present invention optionally include one or more nutritionally acceptable flavors. Flavoring can improve patient compliance by making the composition taste better.

  Oil soluble flavors are known to those skilled in the art and include spearmint oil, dementholed peppermint oil, lemon oil, cinnamon leaf oil, cinnamon bark oil, cardamom oil, caraway oil, coriander seed oil, thyme oil, Contains cinnamon oil, orange oil, star anise oil, dill seed oil, fennel oil, nutmeg oil, benzaldehyde, cinnamaldehyde, sodium formaldehyde sulfoxylate, vanillin, ethyl vanillin, and ethyl acetate. Such flavorings produce clear and homogeneous formulations that appeal aesthetically to consumers.

  The amount of flavoring used typically ranges from about 0.1 weight percent to about 10 weight percent, preferably from about 0.25 weight percent to about 5 weight percent, based on the total weight of the composition. Is within.

  The compositions of the present invention optionally include one or more colorants. Coloring agents can be added to give the product a more aesthetic and / or unique appearance. Suitable colorants include oleoresin turmeric, oleoresin paprika, oleoresin marigold and the like.

  The colorant is about 0.025 weight percent to about 0.25 weight percent, preferably about 0.05 weight percent to about 0.2 weight percent, more preferably about 0.01 weight percent of the total weight of the composition. It can be used in the range of weight percent to about 0.1 weight percent.

  The compositions of the present invention optionally include one or more nutritionally acceptable preservatives. Non-limiting examples of such preservatives include benzoic acid, sodium benzoate, benzethonium chloride, benzyl alcohol, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben and the like.

  The compositions of the present invention optionally include a stabilizer such as an acidifying agent that can be fat-soluble and / or ethanol-soluble. The acidifying agent can be, for example, a fatty acid or a carboxylic acid, typically a mono-carboxylic acid, di-carboxylic acid or tri-carboxylic acid, preferably a mono-carboxylic or dicarboxylic acid. The acidifying agent may contain one or more hydrophilic groups, such as hydroxy groups, preferably one or two hydrophilic groups. Suitable acids for use in the present invention are oleic acid, malonic acid, fumaric acid, famonic acid, maleic acid, D-malic acid, L-malic acid, citric acid, succinic acid, oxalic acid , Benzoic acid or lactic acid, or acids with similar pKa, eg 2-7. Preferred acidifying agents include malonic acid, oxalic acid, citric acid and lactic acid to increase stability during storage and use.

  The composition of the present invention optionally comprises one or more thickeners. Suitable thickeners include those known and used in the art, including, for example, pharmaceutically acceptable polymeric materials. Examples of thickeners include polyacrylate and polyacrylate copolymer resins, polyvinylpyrrolidone, polyvinyl resins, inorganic thickeners, etc., cellulose and their derivatives (eg, methylcellulose, ethylcellulose and propylcellulose); Hydroxyalkyl-cellulose (such as hydroxypropylcellulose and hydroxylpropylalkylcellulose and their salts) are included, preferably hydroxypropylmethylcellulose. If supersaturation is achieved, the thickening agent can act as an anti-deposition agent so that it can be extended for an extended period of time, which can add an additional effective feature to the treatment area.

  Compositions according to certain embodiments of the present application disclose the ratio of each component intended to provide a self-emulsifying drug delivery system when added to a specific volume of water or gastric fluid.

  This formulation of the invention is intended to self-emulsify in-vivo when in contact with gastric juices, so that this is followed by increased absorption and increased bioavailability. It may be in the form of a solution, soft gel or hard shell capsule formulation.

  The composition according to the invention may be used in any suitable manner, for example for oral administration together with water, fruit juice and / or milk as described separately in the application documents. Other suitable orally administrable dosage forms include individual dosage forms such as soft gel and hard shell capsule formulations.

  Suitable encapsulating materials such as gelatin or HPMC capsules can be used. Accordingly, another embodiment of the present invention is a concentrated composition of either a solution or solution / suspension, wherein the composition comprises an individual dosage unit or a plurality of dosage units, eg, a soft gel And as a hard shell capsule formulation. Suitable encapsulating materials such as gelatin or HPMC capsules can be used. Liquid filling / band sealing technology, liquid encapsulating with MicroSpray technology or Quali-Seal technology can be used for encapsulating in hard gelatin capsules.

  The resulting solution can optionally be filled directly into hard gelatin capsules or soft gelatin capsules, or otherwise absorbed on the surface of any adsorbent material and subsequently pressed into a compressed mass Or it can be encapsulated.

  The concentrated solution or solution can be encapsulated by any method known in the art, including plate method, vacuum method, or rotary die method. By the rotary die method, a liquid encapsulating material, eg gelatin, flowing from the elevated tank is formed into two continuous ribbons by a rotary die machine and combined by a twin rotary die. At the same time, a metered filling material is injected between the ribbons at the same time as the die forms a ribbon pocket. These pockets of encapsulant containing filler are then sealed by pressure and heat and the capsule is fed from the machine. Soft gel capsules can be manufactured in different shapes including, among others, circular, oval, rectangular, and tubular shapes. In addition, by using two different color ribbons, two color capsules can be produced.

  Toxicological investigation of NRC-AN-019 shows that the maximum tolerated oral dose of mice is> 5000 mg / kg body weight, and the maximum tolerated oral dose of the formulation of the present invention is 60 mg / kg body weight in beagle dogs. Show.

NRC-AN against the formulation of the present invention in a 1.75 × 10 ⁴ cells / mL CAL-27 (lingual squamous cell carcinoma) cell line using a dilution of 10 μM to 0.0156 μM / mL for 72 hours The MTT (3- [4,5-dimethylthiazolyl-2-yl] -2,5-diphenyltetrazolium bromide) test was performed to compare the activity of the active pharmaceutical ingredients of -0119. And _{an IC 50} value of NRC-AN-019 as the active pharmaceutical ingredient, _{an IC 50} value in the formulations of the present invention, respectively, since it is 1441nM and 864 nm, show a considerably better activity of the formulations of the present invention.

Further comparison of 72 hour MTT assay in 0.312 × 10 ⁵ cells / mL PC3M (prostate cancer) cell line to compare the activity of NRC-AN-019 active pharmaceutical ingredient against the formulation of the present invention The investigation shows that the IC / 50 value of NRC-AN-019 as an active pharmaceutical ingredient and the IC / 50 value in the preparation of the present invention are 4381 nM and 938 nM, respectively, and the activity is nearly 4 times larger than that of the preparation. Became clear.

  The formulations of the present invention have been found to be much more stable during the storage period of the stability test.

  The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalents of the claims are to be embraced within their scope. . The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the principles and scope of the invention.

  FIG. 1 shows a bioavailability study of the formulations of the present invention with respect to the capsule dosage forms disclosed in previous patents and active pharmaceutical ingredients. This study reveals the bioavailability characteristics of NRC-AN-019 of the formulations of the present invention better than those in other forms such as active pharmaceutical ingredients and capsule dosage forms, Availability can be achieved for the therapeutic efficacy of NRC-AN-019. The time required to achieve the highest concentration of the drug is less than the time required to achieve the highest concentration of the active pharmaceutical ingredient for the formulation of the present invention, and the maximum concentration and AUC of the formulation of the present invention is The data suggests that the highest concentration of formulation and active pharmaceutical ingredient and significantly higher than AUC.

  Details of the method of the present invention are provided in the examples set forth below, which are described by way of illustration only and therefore should not be construed to limit the scope of the present invention. Formulations of the invention that can be administered by oral route are performed according to the following methods:

Examples The ingredients exemplified in Examples 1-52 and Comparative Example 1 are expressed in weight percent based on the total weight of the respective compositions.

  In certain embodiments, the present invention provides a method of making a composition, the method comprising intimately mixing NRC-AN-019 and a solvent phase followed by a homogeneous solution until a clear solution is obtained. Adding a lipophilic phase, a cosurfactant and a surfactant phase with stirring under heating to mix or as described in the individual examples.

  The compositions of Examples 1-34 contain fatty acids as the lipophilic phase.

  Composition of Examples 1-3 by diffusing NRC-AN-019 into oleic acid followed by addition of polyoxyl 35 castor oil, polysorbate 80, polyethylene glycol 600 and diethylene glycol monoethyl ether with stirring under heat The thing was manufactured.

  Example 4 by diffusing NRC-AN-019 into oleic acid followed by the addition of polyoxyl 35 castor oil, the respective cosurfactant, polyethylene glycol 600 and diethylene glycol monoethyl ether with stirring under heating. ˜7 compositions were prepared. In Examples 4-7, the co-surfactant was caprylocaproyl polyoxyl-8 glyceride, caprylic glyceride, sorbitan monooleate and PEG-6-glyceryl linoleate, respectively, 19.8% w / w. Include in the amount of w.

  By diffusing NRC-AN-019 into a mixture of soya lecithin and oleic acid followed by addition of polyoxyl 35 castor oil, ethanol and polysorbate 80 with stirring at room temperature, the compositions of Examples 8-10 were prepared. Manufactured. Antioxidants were added to the above mixture. In Example 10, soya lecithin was replaced with egg lecithin.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The compositions of Examples 11-18 were prepared. Butylated hydroxyanisole and butylated hydroxytoluene were added as antioxidants. In Example 17, polyethylene glycol 600 was replaced with ethanol.

Intention for solid individual dosage forms; the composition of the above formulation was scaled up and filled into capsules.
a) Gelatin hard capsules were filled directly and capsules filled with these liquids were sealed using gelatin bands.
b) Hard capsules made of hydroxypropylmethylcellulose were filled directly and the capsules filled with these liquids were sealed using hydroxypropylmethylcellulose bands.
c) Absorb on the surface of Neusilin (magnesium aluminate metasilicate) in the ratio of 3: 1 (Solution phase: Neusilin), followed by simple filling of hard gelatin capsules.
d) Absorb on the surface of Neusilin (magnesium aluminate metasilicate) in a ratio of 3: 1 (solution phase: Neusilin), followed by simple filling of hard HPMC capsules.
e) Encapsulate in soft gelatin capsule by rotary die method.

  While diffusing NRC-AN-019 in the solvent phase followed by stirring under heat to intimately mix until a clear solution is obtained, the lipophilic phase, co-surfactant, surfactant phase and polyvinylpyrrolidone The compositions of Examples 19-22 were made by adding K30. Vitamin E was added as an antioxidant. Sweeteners and flavors were present at 0.5%.

  Diffusion of NRC-AN-019 in the solvent phase, followed by addition of the lipophilic phase, cosurfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained Were used to produce the compositions of Examples 23-25. Butylated hydroxyanisole and butylated hydroxytoluene were added as antioxidants. Sweeteners and flavors were present at 0.05% and 0.5%, respectively.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The compositions of Examples 26 to 28 were produced. Butylated hydroxyanisole and butylated hydroxytoluene were added as antioxidants.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The compositions of Examples 29 and 31 were prepared. Butylated hydroxyanisole and butylated hydroxytoluene were added as antioxidants.

  The composition of Example 30 by diffusing NRC-AN-019 into a mixture of soya lecithin and oleic acid followed by addition of polyoxyl 35 castor oil, polyethylene glycol 600 and polysorbate 80 with stirring under heat. Manufactured. Antioxidants were added to the above mixture.

  Performed by mixing oleic acid, caprylocaproyl polyoxyl-8 glyceride, polyoxyl 35 castor oil, polyethylene glycol 600 and benzyl alcohol, followed by addition of NRC-AN-019 with stirring under heat The composition of Example 32 was made.

  Dissolve some amount of NRC-AN-019 in dimethylacetamide, then add remaining amount of NRC-AN-019 to polyoxyl 35 castor oil, benzyl alcohol, polyethylene glycol 600, sodium lauryl sulfate, d-alpha-tocopherol The composition of Example 33 was made by adding to a mixture of polyethylene glycol 1000 succinate and vitamin E acetate with stirring.

  Some amount of NRC-AN-019 was dissolved in dimethylacetamide and polyethylene glycol 600 followed by stirring the remaining amount of NRC-AN-019 with polyoxyl 35 castor oil, caprylocaproyl polio. The composition of Example 34 was made by adding to a mixture of xyl-8 glyceride and oleic acid. Butylated hydroxyanisole and butylated hydroxytoluene were added to the above.

  The composition of Examples 35-43 containing fatty acids and other lipophilic components as the lipophilic phase.

  Diffusion of NRC-AN-019 in the solvent phase, followed by addition of the lipophilic phase, cosurfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained Were used to produce the compositions of Examples 35-38.

  Diffusion of NRC-AN-019 in the solvent phase, followed by addition of the lipophilic phase, cosurfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained Were used to prepare the compositions of Examples 39-41. In Examples 39 and 40, butylated hydroxyanisole and butylated hydroxytoluene were additionally added as antioxidants.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The compositions of Examples 42 and 43 were prepared.

  The compositions of Examples 44-46 which contain monodiglycerides as the main lipophilic phase.

  The compositions of Examples 44-46 were prepared according to the procedure described in Examples 1-3 by replacing oleic acid with glycerol caprylocaprate as the lipophilic phase.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The composition of Example 47 was produced. Butylated hydroxyanisole and butylated hydroxytoluene were added as antioxidants. In the composition of Example 47, lactic acid was present in an amount of 4.4% w / w.

  NRC-AN-019 is mixed with dimethylacetamide, followed by stirring, dissolved d-alpha-tocopherol polyethylene glycol 1000 succinate, polyethylene glycol 600, caprylocaproyl polyoxyl-8 glyceride, vitamin E acetate The composition of Example 48 was made by adding and ethanol.

  The composition of Example 49 containing vegetable oil as the major lipophilic phase.

  By diffusing NRC-AN-019 with a solvent and then adding the lipophilic phase, co-surfactant and surfactant phase with stirring under heat to intimately mix until a clear solution is obtained The composition of Example 49 was produced.

  The composition of Examples 50-52 containing monoglyceride as the main lipophilic phase.

  By diffusing into the solvent with NRC-AN-019, followed by adding the lipophilic phase, the cosurfactant and the surfactant phase with stirring under heat to obtain a clear solution The compositions of Examples 50-52 were prepared.

  The composition of Comparative Example 1 was prepared by following the procedure of NRC-AN-019. Incorporate sodium lauryl sulfate, polyoxyethylene-polyoxypropylene block copolymer, crospovidone XL, crystalline cellulose and colloidal silicon dioxide into the required amount and sift through an 18-mesh sieve in a mechanical shifter. Subsequently, the mixing procedure was performed in a double cone type mixer. The mixed material was then placed in a mini-roll compressor and the compressed mass was collected in two rows of plastic bags. The compact was recompressed in a roller compressor and then sieved through an 18-mesh sieve. Further, the residue was collected and pulverized, and the sieved granules were put into a compression roller compressor and compressed. To the above contents, the required amount of magnesium stearate was added as a lubricant and mixed moderately, followed by filling the capsule shell.

Bioavailability study of the composition according to the invention Four rats (Wistar albino, male, body weight 120-180 grams) were divided into two study sets (two in each set) and fasted overnight before dosing, provided that The water was free. Sample preparation and subsequent dilution was done with excipients according to the protocol, followed by administration of the sample by the oral route. After dosing, puncture the retroorbital sinus of anesthetized rats (with anesthetic ether) at well-defined intervals of 15, 30, 60, 120, 240, 360, 480, and 720 minutes A blood sample was taken. Blood collection was performed in a centrifuge tube pre-filled with heparin.

  The collected blood sample was subsequently centrifuged and subsequently subjected to an analysis procedure using LCMS technology. The area under the blood drug concentration versus time curve is calculated by the trapezoidal formula. Analysis was performed for AUC (area under the concentration curve), Cmax (maximum concentration) and Tmax (maximum blood concentration arrival time).

  Average AUC (ng hour / mL), Tmax (min) and Cmax (in ng / mL) values from a typical experiment are shown in the table below.

  As can be seen from the above table, the composition according to the invention exhibits high bioavailability (AUC and Cmax). The above table illustrates the bioavailability of the formulations of the present invention, which is improved over the bioavailability of the capsule dosage form and API.

Advantages of the invention a) Phenylaminopyrimidine derivatives (used as BCR-ABL tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia and against other tumors such as head and neck cancer and prostate cancer) For example, a lipid-based oral solution of NRC-AN-019) is manufactured.
b) The advantage is also in achieving better bioavailability than tablet and capsule dosage forms.
c) The advantages further extend to the stability aspect, and it can be seen that the formulation is stable throughout the duration of the stability study.
d) Patient compliance can be achieved with oral solutions because oral solutions are easy to administer and are particularly preferred for children and elderly patients.
e) Industrial applicability: simplicity of scale-up batch manufacturing procedure.
f) To date, no literature has been reported to date regarding the novelty of the present invention with respect to the use of this said derivative in orally administrable oral solutions.
g) The formulation provides a therapeutically effective concentration of an extremely water-insoluble active ingredient.

Claims (20)

(A) A therapeutically effective amount of (3,5-bistrifluoromethyl) -N- [4-methyl-3
-(4-pyridin-3-yl-pyrimidin-2-ylamino) phenyl] benzamide (NRC-AN-019) or a pharmaceutically acceptable salt thereof;
(B) a lipophilic phase;
A pharmaceutical composition for oral administration comprising (c) at least one pharmaceutically acceptable surfactant; and (d) a pharmaceutically acceptable water-miscible solvent. Component (a) is present in an amount of 0.1 to 20 weight percent relative to the total weight of the composition;
Component (b) is present in an amount of 10 to 75 weight percent relative to the total weight of the composition;
Component (c) is present in an amount of 4 to 70 weight percent relative to the total weight of the composition;
Component (d) is present in an amount of 5-30 wt percent relative to the total weight of said composition,
The pharmaceutical composition according to claim 1. 3. A pharmaceutical composition according to claim 1 or 2 comprising a Form I, Form II or Form III polymorph of NRC-AN-019.   4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the lipophilic phase comprises triglycerides, diglycerides, monoglycerides, fatty acids, fatty acid derivatives, or mixtures thereof. It said fatty acid is a long chain fatty acid, the pharmaceutical composition according to claim 4. The lipophilic phase, relative to the total weight of the lipophilic phase comprises a C ₁₈ unsaturated fatty acid residues in an amount of at least 20 weight percent, the pharmaceutical composition according to any one of claims 1 to 5 object. The lipophilic phase, based on the total weight of the lipophilic phase comprises a saturated fatty acid residue in an amount of 50 wt% or less, according to claim 1 to a pharmaceutical composition according to any one of 6.   8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the at least one surfactant comprises a major surfactant and one or more co-surfactants. The pharmaceutical composition according to any one of claims 1 to 8, wherein the at least one surfactant comprises a polyoxyethylene glycolated vegetable oil . The cosurfactant is present in an amount of 2 to 60 weight percent relative to the total weight of the composition, the pharmaceutical composition according to claim 8 or 9. It said auxiliary surfactant comprises polyoxyethylene glyceride pharmaceutical composition according to claim 8, 9 or 10.   12. A pharmaceutical composition according to any one of the preceding claims, wherein the water miscible solvent acts as a carrier medium for NRC-AN-019.   The pharmaceutical composition according to any one of claims 1 to 12, wherein the water-miscible solvent is an α-hydroxy-ω-hydroxypoly (oxy-1,2-ethanediyl) derivative.   The pharmaceutical composition according to claim 13, wherein the α-hydroxy-ω-hydroxy poly (oxy-1,2-ethanediyl) derivative is polyethylene glycol 600. Further including an antioxidant, a pharmaceutical composition according to any one of claims 1 to 14. Further including a sweetener, a pharmaceutical composition according to any one of claims 1 to 15. Further including a flavoring, pharmaceutical composition according to any one of claims 1 to 16.   18. A pharmaceutical composition according to any one of the preceding claims, which takes the form of a solution, a soft gel or a hard shell capsule formulation.   Use of a pharmaceutical composition as defined in any one of claims 1 to 18 in the manufacture of a pharmaceutical composition for the treatment of cancer. Mixing NRC-AN-019 with a water-miscible solvent,
Addition of lipophilic phase,
Including the addition of a surfactant and optionally a co-surfactant, and stirring under heating,
A method for producing a pharmaceutical composition as defined in any one of claims 1 to 17.